Liver transplantation for alcoholic liver disease.

In many patients, long-term heavy drinking leads to chronic liver disease, liver failure, and even death. Orthotopic liver transplantation (OLT) is the only definitive treatment for end-stage liver disease, including alcoholic liver disease (ALD). Because of a shortage of donor organs, OLT for ALD patients remains controversial out of concerns that patients may resume drinking, thereby harming the transplanted organ. Therefore, transplant centers conduct careful screening procedures that assess patients' coexisting medical problems and psychosocial status to identify those patients who are medically most suited for the procedure and who are most likely to remain abstinent after OLT. Studies assessing the outcomes of ALD patients after OLT found that the survival rates of the transplanted organ and the patient were comparable to those of patients with nonalcoholic liver disease and that relapse rates among the ALD patients were low. Similarly, ALD patients and patients with other types of liver disease had comparable rates of compliance with complex medication regimens after OLT. Enhanced efforts to identify risk factors for relapse among OLT candidates with ALD and to target interventions specifically to those patients who are at high risk of relapse may further improve patient outcome and enhance the acceptance of OLT for alcoholic patients in the general population.

P opulation-based surveys indicate imately 100,000 per year) are either tomatic fatty liver (i.e., steatosis) or that 68 percent of adult Americans directly or indirectly attributable to abnormalities of liver enzymes to drink at least one alcoholic beverage alcohol abuse (Hoofnagle et al. 1997). end-stage liver disease-that result per month. About 10 percent consume from alcohol ingestion. Women in more than two drinks per day, which is • Only about 10 percent of all general show greater susceptibility a commonly used definition of "heavy drinkers account for 50 percent of to ALD than men, and African drinking" (Hoofnagle et al. 1997). How-the total alcohol consumption in Americans show greater susceptibil ever, substantial differences exist in the the United States per year (Li 1997). ity than Whites. prevalence of heavy drinking among • Among heavy drinkers, liver disease population subgroups. For example, • About 13.8 million people in the 18 percent of men but only 3 percent United States meet the diagnostic is highly prevalent. Thus, 90 to 100 of women are classified as heavy drinkers, criteria for alcohol abuse or depen and heavy drinking is more common dence specified in the fourth edition ABHINANDANA ANANTHARAJU, M.D., is among Whites than among African of the American Psychiatric Association' s a fellow, and DAVID H. VAN THIEL, M.D., Americans or Hispanics. Heavy drinking Diagnostic and Statistical Manual of is a professor of medicine and surgery and and its consequences are important Mental Disorders (Grant et al. 1994). director of Liver Transplantation and public health problems, as illustrated Hepatology. Both are associated with the by the following statistics: • About 15 percent of U.S. alcoholics Liver Transplant Program in the Division eventually will develop alcoholic liver of Gastroenterology, Hepatology, and • Five percent of the deaths occurring disease (ALD), a broad spectrum of Nutrition, at Loyola University Medical annually in the United States (approx-liver injuries-ranging from asymp-Center, Maywood, Illinois. percent of heavy drinkers have steatosis, 10 to 35 percent have alcoholinduced inflammation of the liver (i.e., alcoholic hepatitis), and 8 to 20 percent have alcoholic cirrhosis (McCullough 1999).
• The 5-year and 10-year survival rates for patients with alcoholic cirrhosis are 23 percent and 7 percent, respec tively (McCullough 1999). These rates are significantly worse than survival rates for patients whose cir rhosis was not caused by alcohol.
Alcohol consumption is one of the leading causes of chronic liver disease in the United States and worldwide. In Western countries, alcohol is the major causative factor in about 50 percent of deaths from end-stage liver disease (McCullough 1999). To date, liver trans plantation (also known as orthotopic 1 liver transplantation [OLT]) is the only definitive treatment for end-stage liver disease. However, OLT for patients with ALD continues to be controversial because of the ever-increasing demand for donor organs and the inadequate rate of organ donation, combined with concerns that alcoholic patients might relapse to drinking, thereby damaging the transplanted liver.
This review discusses the patterns and controversies relating to liver transplan tation in patients with ALD. After pro viding some historical perspective and summarizing the current status of OLT in these patients, the article discusses elements of the pretransplantation eval uation that can help identify suitable patients for the procedure. Outcomes for ALD patients who have received liver transplants are reviewed, and the ethical issues surrounding this procedure in alcoholic patients are discussed. This article concludes by summarizing future research directions that might improve the outcomes of liver transplants in alcoholics and thereby resolve some of the ethical concerns. 1 Orthotopic means "in the normal or usual place."

Historical Perspective
Before the National Institutes of Health (NIH) Consensus Conference on Liver Transplantation in 1983, OLT rarely was performed in patients with ALD. The Consensus Conference concluded that ALD is an appropriate indication for OLT if the patient is judged likely to abstain from alcohol after transplan tation (Lucey 2001). This conclusion, which was adopted by many transplant centers, led to an increase in the num ber of transplants performed for ALD. A report by Starzl and colleagues (1988) made the most convincing argument for OLT for ALD patients, demonstrating that 73 percent of ALD patients who had received a liver transplant still were alive 1 year after the procedure, and that only 3 percent of those patients had relapsed to alcoholism. Based on these findings, in 1991 the Health Care Financing Administration (HCFA) identified ALD as one of the seven con ditions for which it approved payment for OLT, but the HCFA recommended a "significant" period of abstinence for alcoholics before undergoing the proce dure as well as the availability of a rea sonable social support system.
To identify alcoholic patients suitable for OLT, Beresford and colleagues (1990) proposed a selection method that included measures of the likelihood of abstinence, such as the extent to which alcohol dependence was recognized by the patient and his or her family, the patient's degree of social stability, and the nature and extent of lifestyle changes conducive to long-term abstinence. Using this selection method, Lucey and colleagues (1992) reported on a multidisciplinary collaboration of transplant hepatologists, surgeons, and psychiatrists that identified psychosocial predictors of long-term sobriety and compliance after OLT in alcoholics. (These predictors are sum marized in the University of Michigan Alcoholism Prognosis Scale, which is discussed later.) These researchers reported that ALD patients judged suitable using these criteria had outcomes after OLT that were similar to outcomes for trans plant patients with non-alcohol-related liver disease (non-ALD). People who were judged suitable for OLT included patients with severe end-stage liver disease without an available alternative therapy, who showed a clear understanding of the risks and benefits of the procedure, had a favorable psychiatric assessment including acceptance of alcoholism, and had favorable prognostic factors for future sobriety.
The minimal listing criteria estab lished by the United Network for Organ Sharing (UNOS) in 1996 do not include an absolute requirement for a 6-month period of abstinence before ALD patients are listed as candidates for OLT (UNOS 1996). Furthermore, a 1996 NIH workshop on OLT for patients with ALD concluded that liver transplantation provides a good outcome in alcoholic patients and that relapse rates after OLT were lower if the patients had success fully completed conventional alcohol rehabilitation programs prior to OLT (Hoofnagle et al. 1997).
ALD now is widely accepted by many transplant centers as a valid indi cation for OLT, provided the transplant team caring for the patient can reason ably expect him or her to remain absti nent after the transplant.

Current Status
According to the UNOS database, 41,734 liver transplants using organs from dead donors (i.e., cadaveric trans plants) were performed in the United States between 1992(UNOS 2002. Of those, 12.5 percent were per formed in patients with ALD, and 5.8 percent were performed in patients with ALD and a concurrent infection with the hepatitis C virus (HCV were on the waiting list for a cadaveric liver transplant; of these, about 14.1 percent had ALD, and 6.2 percent had combined ALD and HCV infection. Overall, the number of liver trans plants performed annually for ALD has been relatively constant for many years (see the accompanying figure), but the number performed because of chronic HCV infection has increased annually, as has the number of liver transplants for combined ALD and HCV infection.

Pretransplant Evaluation of Patients With ALD
To ensure the success of liver transplanta tion, ALD patients are required to undergo a thorough evaluation to determine whether they are suitable candidates. This evaluation addresses any coexisting medical problems that might influence the outcome of the transplant and includes a psychological evaluation to identify those patients who are most likely to remain abstinent and comply with the medical regimen after the procedure.

Coexisting Medical Problems
Alcohol affects many organ systems in addition to the liver. For example, as described by Keeffe (1997) and Neuberger and colleagues (2002), alcohol abuse can lead to: • Damage of the heart muscles (i.e., cardiomyopathy) and skeletal mus cles (i.e., skeletal myopathy).
• Central and peripheral nervous system dysfunction.
• Cancers of the airways and diges tive tract.
These conditions, particularly if they are severe, can complicate the manage ment of patients with ALD both before and after OLT, and some may even be contraindications for OLT (Keeffe 1997). However, some of these alcohol-induced conditions (e.g., cardiomyopathy and acute pancreatitis) can be reversed by abstinence, and when such a reversal occurs, these conditions do not affect the decision on a patient's suitability for a transplant.
The clinical approach to evaluat ing a patient for OLT also may be markedly altered by other disorders that can coexist with ALD, such as infec tion with hepatitis viruses, particularly HCV, and the presence of liver cancer. The impact of all these coexisting condi tions is discussed in the sections to follow.
Cardiomyopathy. The exact preva lence of heart disease in patients with end-stage ALD is unknown (Keeffe 1997). Overall, cardiomyopathy is far more common in actively drinking alcoholics than in abstinent alcoholics (Campbell and Lucey 1996). In general, alcohol-related cardiomyopathy rarely is a reason for refusing liver transplan tation (Lucey 2001). Anecdotal evidence suggests that coronary artery disease (CAD) may be more prevalent than cardiomyopathy in patients with ALD (Keeffe 1997). To identify either condi tion in liver transplant candidates, many transplant centers routinely assess cardiac function through noninvasive tests (e.g., electrocardiography, echocar diography, and stress tests) as part of their pretransplant evaluations (Neu berger et al. 2002). A more invasive technique, coronary angiography, uses X rays to visualize the structure of the heart and blood vessels following the injection of a contrast medium, and can identify more patients with CAD than the various noninvasive cardiac tests used (Keeffe 1997). Although CAD is not a reason to refuse a patient a transplant because it usually can be reversed by abstinence, the condition can create problems if it has not been identified prior to the OLT.

Skeletal Myopathy.
Muscle damage occurs in up to 42 percent of alcoholic patients with ALD; 46 percent of actively alcoholic men show changes in muscle cell structure indicative of skeletal myo pathy (Keeffe 1997). This condition is manifested as muscle weakness, muscle pain, and abnormal tests for muscle enzymes; the disorder results from a combination of alcohol's direct effects on the muscles, malnutrition, and alcoholrelated inflammation or degeneration of nerves (i.e., neuropathy) (Keeffe 1997). The presence of skeletal myopathy appears to depend on how much alco hol the person has consumed over his or her lifetime (Keeffe 1997;Campbell and Lucey 1996). In general, skeletal myopathy is not a contraindication for OLT, and severe myopathy is unusual in potential alcoholic OLT candidates.
Pancreatitis. Chronic inflammation of the pancreas is five times less common in people with ALD than in alcoholics without liver disease; the reasons for this difference are not known (Keeffe 1997). In general, pancreatitis is not considered a contraindication for liver transplantation; however, severe chronic pancreatitis can adversely affect the absorption of medications that prevent the immune system from rejecting the transplanted liver. Therefore, patients with pancreatitis may require closer monitoring for rejection of the trans planted organ as well as administration of higher doses of antirejection medica tions to achieve effective concentrations.

Malnutrition.
Malnutrition occurs in many, if not all, patients with ALD. Causes of malnutrition include a poor diet; increased breakdown (i.e., catabolism) of carbohydrates, proteins, and lipids in the body; as well as impaired absorption of nutrients, interruption of the bile flow (i.e., cholestasis), reduced pancreatic function, bacterial over growth, and/or alcohol-induced injury to the intestinal mucosa (Matos et al. 2002). In particular, alcoholics com monly show deficiencies in various vitamins, including thiamine, which is essential for normal brain functioning. Therefore, alcoholics with ALD rou tinely should be prescribed thiamine and multivitamins. Severe malnutrition is associated with a poorer prognosis after OLT and may require postpone ment of the procedure until the patient has achieved a better state of nutrition (Matos et al. 2002). The nutritional sta tus of OLT candidates can be improved by providing additional nutrition directly into the gastrointestinal tract (i.e., by enteral feeding). Moreover, nutritional support before and after the transplant can improve the clinical outcome after OLT (Matos et al. 2002).
Neurological Deficits. Chronic alco holism may lead to neurological deficits through alcohol's direct actions on the brain and nerve fibers, which can result in structural damage (Lucey 2001;Keeffe 1997). In patients with ALD, however, neurological deficits also can result from a condition called hepatic encephalopathy, which is caused by the damaged liver's inability to remove sub stances from the blood that can inter rupt brain function. In these patients, it is difficult to distinguish deficits resulting from alcohol's direct effects on the brain from those resulting from hep atic encephalopathy. Severe neurological deficits may contraindicate liver trans plantation because the patient may not be able to comply with post-transplant medication regimens and because OLT may not improve the patient's quality of life significantly. Therefore, most trans plant centers routinely perform brainimaging analysis of OLT candidates to identify any structural damage that may exist before the transplant and which could affect the patient's out come after the transplant (Lucey 2001).
Abnormal Bone Structure. Patients with ALD are prone to bone loss because of impaired activity of the bone-producing cells; reduced activity of the ovaries or testes, which produce hormones regulating bone formation; reduced body mass index; and limited physical activity (Keeffe 1997). Between 10 and 42 percent of patients with ALD have a reduced bone density, which can lead to a condition called osteopenia (or, in severe cases, osteo porosis), which is characterized by bone softening, accompanied by weak ness and susceptibility to fractures. Therefore, routine bone mineral den sity measurements and, in appropriate cases, blood tests assessing calcium metabolism and ovarian or testicular function are recommended in patients with ALD. Treatment with calcium and vitamin D (which regulates cal cium metabolism) can improve bone mineral density in patients with ALD (Rouillard and Lane 2001). Other approaches used to improve bone min eral density in patients with non-ALD include administration of hormones to compensate for reduced ovarian or tes ticular activity as well as treatment with other compounds that influence cal cium metabolism (i.e., calcitonin and biphosphonates) (Rouillard and Lane 2001). The effectiveness of these approaches in alcoholics, however, has not been studied specifically.
HCV Infection. About 20 to 30 per cent of patients with ALD are infected with HCV (Keeffe 1997), and the rate of progression of liver disease and the long-term outcome are worse for these patients than for alcoholics not infected with HCV (Peters and Terrault 2002). In addition, the most commonly used treatment for HCV infection-an agent called interferon-is less effective in active alcoholics, probably because the antiviral activity of interferon is decreased in these patients (Peters and Terrault 2002). HCV infection in alco holic patients also influences the out come after liver transplantation; in fact, the transplanted liver is much more likely to be damaged by renewed HCV infection in these patients than by a relapse to alcohol abuse.
Patients with ALD who also are infected with the hepatitis B virus face challenges similar to those experienced by ALD patients with HCV infection.
In general, patients with liver disease resulting from alcohol abuse and coex isting viral infection appear to have a worse prognosis than patients with liver disease resulting from only one of these factors (Bellamy et al. 2001).
Liver Cancer. Patients with alcoholic cirrhosis have an increased prevalence of liver cancer (i.e., hepatocellular car cinoma, or HCC) (Peters and Terrault 2002;Stickel et al. 2002). These tumors can substantially influence the patient's outcome after OLT because of the risk that they will recur. The presence of HCC itself is not a contraindication for OLT, because patients can have a reasonably good prognosis after OLT if they have only small tumors (≤ 5 centimeters [cm] in diameter) and/or fewer than four tumors of 3 cm or less each that have not spread to major blood vessels or outside the liver. Studies have found that cancers other than HCC (e.g., cancers of the airways and digestive tract or lymph node tumors) occur significantly more com monly in patients undergoing OLT for ALD than for non-ALD and are a major cause of illness and death late after OLT for ALD (Bellamy et al. 2001). To rule out the presence of a coexisting liver cancer, routine hepatic imaging studies are recommended as part of a pretrans plant workup for all OLT candidates. Similarly, it is imperative that patients being considered for OLT undergo a thorough pretransplant screening for tumors outside the liver as well as a regu lar evaluation after the transplantation.

Psychiatric Evaluation
For OLT to be successful in alcoholic patients it is essential that the patients remain abstinent after the transplant and comply with the demanding medi cal regimen (e.g., consistently take the necessary antirejection medications). Routinely conducting psychiatric eval uations before patients are included on the list of candidates for transplantation may identify those who are most likely to fail these criteria. 3 In a survey using a five-point questionnaire, staff at 93 percent of transplant centers felt that a psychiatric evaluation was an important component in the pretransplant workup, and staff at 83 percent of the centers reported routinely using a psychiatrist or addiction specialist during the pretransplant evaluation (Everhart and Beresford 1997). In most cases, the psychiatric evaluation includes assess ments of the patient's socioeconomic condition as well as of underlying psy chiatric disorders, job status, number and duration of prior attempts at absti nence, and use of other drugs. During this evaluation, the psychiatrist routinely interviews both the patient and one or more family members, and estimates the risk of post-transplant alcohol relapse.
One measure that has been proposed to predict post-transplant sobriety is the University of Michigan Alcoholism Prognosis Scale (MAPS), which assesses a variety of factors, including: • The patient's and family's recogni tion and acceptance of alcoholism.
• Four prognostic factors indicating sobriety, including involvement in activities that can substitute for drink ing (e.g., sports), negative behavioral consequences of alcoholism, presence of hope/self-esteem, and availability of social relationships.
• Social stability factors, such as a stable job, residence, and marriage, or living with another person.
Data on the effectiveness of the MAPS are equivocal, however. In a prospective study, patients identified as suitable OLT candidates based on their MAPS scores had a low incidence of pathological drinking 3 years after liver transplantation (Beresford et al. 1992). Conversely, a retrospective study con ducted 5 years after ALD patients had received transplants showed that their pretransplant scores did not predict continued sobriety (Lucey et al. 1997).
Some researchers consider an abstinence period of 6 months prior to OLT a pre dictor of long-term abstinence (Beresford and Everson 2000;Weinrieb et al. 2000). Some transplant programs and insurance companies insist on an absolute 6-month period of abstinence before a patient with ALD can be listed for liver transplanta tion. This 6-month rule remains contro versial, however, and appears to be arbi trary. Some studies favoring the 6-month rule have demonstrated that patients who are abstinent for less than 6 months have a greater relapse rate (Beresford and Everson 2000;Weinrieb et al. 2000), but these studies only examined short periods of time, included only a small number of patients, and did not include control subjects. In contrast, many retrospective and prospective studies have demon strated that the 6-month rule does not predict long-term sobriety after OLT (see table 1). As a result, the current minimal listing criteria for liver transplantation proposed by UNOS do not require a 6 month period of abstinence before listing ALD patients for liver transplantation.
As an alternative to the 6-month abstinence requirement for predicting abstinence after OLT, Yates and colleagues (1998) proposed a High Risk Alcoholism Relapse (HRAR) scale, which is based on the patient's history of heavy drinking, usual number of drinks, and number of prior alcoholism inpatient treatment episodes. Initial studies have demon strated that patients with low HRAR scores had a low relapse rate and could be deemed eligible for transplant with out a pre-OLT 6-month period of absti nence (Yates et al. 1998). A subsequent study by the same research group, how ever, showed that the HRAR scale had little ability to predict continued sobri ety after OLT (DiMartini et al. 2000).

Outcomes for ALD Patients After OLT
When assessing the long-term outcome for patients receiving OLT or any other kind of transplant, researchers and clin icians evaluate numerous factors in addition to the survival of the patient, including how long the transplanted organ continues to function (i.e., graft survival) and the patient's quality of life. Out of concerns that ALD patients may resume drinking after OLT and thereby damage the transplanted liver, investigators frequently assess graft sur vival in these patients. These assessments have found that the graft-survival rate in patients with ALD is comparable to that of patients with non-ALD (see table 2) (UNOS 2002). This finding suggests that the ALD patients are not more likely to relapse (or that their alcohol consumption may not be likely to damage the transplanted liver). In fact, the 1-and 3-year graft-survival rates in patients with ALD are above the average graft-survival rates for all diagnoses for which OLTs are per formed (see table 2). Moreover, the pres ence of a concurrent HCV infection does not appear to alter the 1-, 3-, and 5-year graft-survival rates in patients with ALD. However, a study by Neu berger and colleagues (2002) demon strated that patients undergoing OLT for combined ALD and HCV infection were more likely to develop hepatic fibro sis than were patients with either ALD or HCV infection alone. Additional survival rates reported by various groups of investigators are summarized in table 1.
A few retrospective studies have been performed in abstinent patients who underwent OLT for ALD. These patients' livers subsequently were removed and examined for the presence of hepatitis caused by alcohol. Again, the presence of hepatitis appeared to have no impact on outcome, with the survival and relapse rates of these patients comparable to those of patients with alcoholic cirrhosis alone (Lucey 2002). No specific studies have assessed OLT survival rates and sobriety in patients with acute alcoholic hepatitis.

Quality of Life
The term "quality of life" encompasses various factors that influence a patient's subjective well-being, such as medical status, social status, employment status, or relationships. Overall, the physical and psychological outcomes for ALD patients after OLT appear similar to those of non-ALD patients (Pereira et al. 2000). However, patients who relapse to alco employment rates for ALD patients had relapse is controversial, varying from hol use after receiving transplants have increased only marginally (i.e., to 33 any use of alcohol after OLT to alcohol poorer post-transplant scores on percent). Furthermore, no associations abuse resulting in physical and social quality-of-life measures than patients who were found between alcohol use and consequences or rehospitalization for do not relapse (Coffman et al. 1997). employment status after OLT or alcoholism (Fuller 1997). Although ALD patients in general have prob-between pre-and post-transplant employany alcohol use after OLT should be lems keeping a job and fulfilling their ment and sobriety. With all these findings viewed as serious because it is the earliest job requirements (i.e., they have low it is important to note, however, that the indicator of high risk for the long-term levels of occupational functioning). employment status reported in many viability of the graft , OLT can ameliorate these problems to studies is based on self-reports, which have not all relapses may be harmful to the a certain extent. Nevertheless, an analysis substantial limitations (i.e., respondents transplanted liver and the patient. The combining the findings of several stud-may not always answer truthfully or may occasional use of small amounts of ies (i.e., a meta-analysis) demonstrated not accurately recall the information). alcohol (i.e., a "slip") is not considered that the employment status of ALD harmful and should not be treated puni patients both before and after trans plantation is dismal (Bravata et al. Relapse to Alcohol Use tively (Fuller 1997). These slips may not progress to an overt relapse that is 2001). Before transplantation, 29 per-As mentioned previously, an important potentially harmful to the new liver. cent of ALD patients and 59 percent of concern in selecting alcoholic candidates Because of the differing definitions non-ALD patients were employed. At for OLT and evaluating the outcome of relapse, the reported relapse rates vary 3 years after the OLT, employment of the procedure is the likelihood of a widely across studies (see table 1), whereas rates for non-ALD patients had increased relapse to alcohol use after the trans-the rates of graft dysfunction resulting substantially (i.e., to 80 percent), whereas plant. The definition of an alcohol from alcohol relapses are more consistent regardless of the definition of relapse used. Furthermore, the transplanted liver is rejected at a similar rate in both abstinent and nonabstinent alcoholic patients (Campbell and Lucey 1996). This rejec tion reaction can occur if the patient does not consistently take necessary antirejection medications. Studies have found that among patients receiving OLT for ALD, the overall rate of non compliance with the antirejection med ications is as high as 16 percent (Berlakovich et al. 2000). However, alcohol relapses per se do not appear to influence the patients' compliance with their medication regimen. Interestingly, a meta-analysis found that ALD and non-ALD patients reported similar rates of alcohol use at 6 months (4 percent and 5 percent, respectively) and 12 months (17 percent and 16 per cent, respectively) after OLT (Bravata et al. 2001), although heavy drinking was more common in patients who had undergone liver transplantation for ALD. At 7 years after OLT, 32 percent of ALD patients reported drinking some alcohol (Bravata et al. 2001). As previously mentioned, continued alco hol use after OLT puts the patient at risk for renewed ALD. Studies have found, however, that from a purely bio logical perspective, recurrent ALD is less prevalent and less severe after OLT than recurrent liver disease from other causes (e.g., reinfection with a hepatitis virus) (Bellamy et al. 2001).
The reported relapse rate is influ enced not only by the different defini tions of relapse but also by the method used to identify a relapse. The most useful identification method appears to be a clinical interview conducted by a transplant psychiatrist or a question naire interview by an assistant . Biochemical markers (e.g., alcohol levels in the blood, urine, or breath, or tests for the presence of certain enzymes) as well as regular liver biopsies are less effective at identifying relapses (Neuberger et al. 2002;Campbell and Punch 1997). Relapse rates are highest during the ini tial 6 months after the transplant and decline after this period (Platz et al. 2000). About 95 percent of all relapses occur in the first 2 years after OLT.

Predictors of Relapse After OLT
Most patients with ALD are less severely dependent on alcohol than patients attending alcohol clinics (Howard and Fahy 1997), possibly because patients who do not exhibit symptoms of severe alcohol dependence are at greater risk of developing ALD because they can sustain continuous alcohol consumption over many years (Wodak et al. 1983). The patient's premorbid social stability and Alcoholics Anonymous attendance record before OLT are important determinants of sustained abstinence after the procedure (Howard and Fahy 1997;Beresford 1997). Such factors can be assessed prior to a transplant using measures such as the Strauss-Bacon and Skinner indices, but few transplant centers report using these indices (Beresford 1997).
Another factor influencing relapse risk is the presence of other psychiatric disorders. The prevalence of preexisting psychiatric disorders in ALD patients is unknown. The few studies conducted in this patient population appear to show a higher rate of major psychiatric disorders among ALD patients than in the general population (Beresford 1997). However, major depressive disorders or schizophrenic conditions, which would indicate a greater risk of relapse after OLT, occur only rarely (Howard and Fahy 1997;Beresford 1997). The pres ence of post-traumatic stress disorder also increases the risk of alcohol relapse.
Coexisting dependence on drugs other than alcohol also is associated with higher rates of alcohol relapse. Studies have found that although 30 to 50 percent of patients who are dependent only on alcohol achieve sustained absti nence after alcoholism treatment, only 10 percent of patients who used more than one drug achieved abstinence (Beresford 1997). 4 A prolonged period of documented abstinence from all drugs can indicate a low risk of relapse. Conversely, multiple failed attempts at alcohol abstinence before OLT are con sidered an indication that the prognosis for sustained sobriety after the trans plant is poor (Beresford 1997).
Based on long-term studies of alco holism remissions and relapses, Vaillant (1995) proposed four prognostic fac tors that indicate a favorable outcome: the patient's involvement in activities that can substitute for alcohol, a caring 4 The failure of investigators to distinguish between alcohol dependence and multiple-drug dependence in patients with ALD is one of the reasons for the variable relapse rates after OLT. *Necrosis is tissue death occurring in groups of cells; cholangitis is an inflammation of the bile ducts; biliary cirrhosis is an inflammation of the liver resulting when bile flow through small ducts in the liver is obstructed; autoimmune diseases are those conditions in which the body's immune system erroneously attacks the body's own cells.

Predictors of Relapse in Patients With Alcoholic Liver Disease Following Liver Transplantation
Psychiatric comorbidity Poor self-image Social instability Associated chronic illness Prior rehabilitation attempts Abuse of more than one drug Lack of involvement with other activities Lack of coordinated care relationship with another person, a source of hope or improved self-esteem, and negative behavioral reinforcement for subsequent drinking (e.g., the devel opment of acute pancreatitis). When at least two of these factors are present, the patient is likely to remain abstinent for 3 or more years. If none of these factors or only one of them applies, the patient is likely to relapse within 2 years. Individual transplant centers also assess long-term abstinence among their patients. Based on their findings, UNOS developed the following guide lines for considering individual alcoholic patients for liver transplantation (UNOS 1996;Vaillant 1995): • A few months of sobriety as a test of short-term compliance (UNOS does not require a 6-month period of abstinence).
• Presence of a supportive social net work at home.
• Absence of comorbid risk factors.
• A clinical impression that the patient has been compliant in the past.
Some transplant centers have used contingency contracting as a method to improve long-term abstinence (DiMartini et al. 2002). With this approach, the patient and the center enter a formal agreement that specifies the consequences of certain actions of both parties. No studies to date have assessed the efficacy of this strategy, however.
Several investigators have proposed additional risk factors for an alcohol relapse (also see the textbox). A study by Platz and colleagues (2000) suggested that these risk factors include being female, having a poor social environ ment, having poor personal stability as assessed by a psychologist, and com pleting less than 6 months of absti nence. DiMartini and colleagues (2001) identified a history of other drug use, a family history of alcoholism, and previous experience with alco holism treatment as risk factors associ ated with a higher incidence of alcohol relapse. These investigators did not find any relationship between a prior psychiatric disorder and abstinence at 6 months after the transplant.

Types of Liver Damage During an Alcohol Relapse
Although it is not necessary to take a tissue sample (i.e., biopsy) of the liver to make a diagnosis of recurrent ALD in patients who have relapsed to alcohol use, researchers have examined changes in liver structure (i.e., histological changes) that occur in these patients. These analyses found that the histological fea tures of recurrent ALD that affect the transplanted liver are similar to those of ALD in the native liver (Lee 1997). The major histological changes seen with recurring ALD in transplant patients are steatosis, which is found in 83 percent; steatosis accompanied by inflammation (i.e., steatohepatitis), found in 10 percent of cases; fibrosis in certain areas of the liver, which occurs in 28 percent of patients; and cirrhosis, found in 23 percent of patients. Other less commonly seen changes include enlarged mitochondria 5 in 14 percent of cases, excess levels of iron (i.e., siderosis) in the liver cells in 24 percent of cases, and interruption of the bile flow within the liver. These changes are not specific for ALD, and the physician therefore must exclude the presence of other diseases (e.g., viral infection).

Management of Alcoholic Patients After an OLT
With the exception of patients who are dependent on other drugs in addition to alcohol, ALD patients do not have a higher incidence than non-ALD patients of pre-or postoperative psychiatric problems that would necessitate addi tional treatment (Howard and Fahy 1997). However, ALD patients at high risk for relapse should be followed closely, and regular psychiatric followup should be considered in such cases.
To date, no controlled studies have evaluated specific treatment methods for managing relapse after liver trans plantation. The alcoholism treatment approaches used in the general popula tion are probably applicable to these patients as well, with close monitoring by the transplant psychiatrist/psychologist and physician. Several studies have demonstrated that the involvement of a transplant psychiatrist or psychologist both before and after OLT reduces the alcohol relapse rate after transplantation (Lucey et al. 1992;Berlakovich et al. 1994Berlakovich et al. , 2000. Several investigators have attempted to study the effectiveness of motiva tional enhancement therapy in patients who relapse after liver transplantation (DiMartini et al. 2002). The results of such studies are unclear, however, because few patients enroll in these studies and because other problems are associated with the care of such patients.
Another approach to achieving abstinence in alcoholic patients, administering the medication disulfi ram, which serves to deter people from drinking by causing unpleasant effects when combined with alcohol, is not recommended in patients after OLT because disulfiram has toxic effects on the liver.

Ethical Issues Associated With OLT for ALD Patients
Although most people in the popula tion consume alcohol at least occasion ally, alcoholism and the diseases caused by it continue to carry a stigma among the general public. This is true particu larly for ALD, and no other alcoholinduced organ damage is viewed so negatively. Many people have a bias against liver transplants in alcoholics, resulting at least in part from the contin ued organ shortage and ever-increasing demand for donor organs, which neces sitates rationing of the donor organs. For example, some people consider ALD a self-inflicted disease and there fore propose that ALD patients have lower priority on transplant waiting lists. This attitude is reflected in an opinion poll conducted in Great Britain, which showed that both the general public and family physicians believed that alcoholic patients should have a lower priority than others for OLT (Neuberger et al. 1998). Similar results were reported in Oregon, where the general public was asked to allocate priorities for 714 disorders or treatments. The respon dents rated the priority of OLT for non-ALD patients at a moderate level (364 out of 714), but gave a very low priority (695/714) to OLT for ALD (McMaster 2000). Transplant psychia trists and psychologists, however, have a more favorable opinion on OLT for alcoholics. For example, in a survey of these health care professionals from 14 academic liver transplant centers in the United States, a consensus favored offer ing further alcoholism treatment to patients who continued to use alcohol rather than refusing OLT outright (Snyder et al. 1996).
Researchers and clinicians originally thought that ALD patients would have poorer graft and patient survival rates than non-ALD patients, but such a dif ference has never been documented. Neither has the assumption of high relapse rates in ALD patients been con firmed. Relapse rates following OLT are lower than in patients undergoing alcoholism treatment, and serious relapses that adversely affect the trans planted liver or the patient are uncom mon (see table 1). In contrast, patients who receive OLT because of an infec tion with hepatitis B or C viruses always experience disease recurrence and have an increased likelihood of losing the transplanted liver primarily because of this recurrence. Another concern, that patients with ALD would not be able to comply with the antirejection medication regimen, also has not been confirmed. Graft-rejection rates are similar for patients trans planted for ALD and those trans planted for other types of liver disease, which indicates comparable rates of compliance with the antirejection med ications. Finally, it was anticipated that ALD patients would utilize more resources, thereby incurring higher costs, than non-ALD patients, but again this assumption never has been corroborated by research evidence (Campbell and Lucey 1996).
In contrast to these negative assump tions regarding the outcome of OLT in ALD patients, many clinicians argue that ALD is an excellent indication for liver transplantation. For example, the overall improvement in the status of patients with ALD after OLT, includ ing the improvement in productivity, supports considering such patients for liver transplantation. Moreover, the long-term costs of OLT and the subse quent management of the alcoholic patient probably are lower than the costs of managing alcoholism and ALD without transplantation. This assump tion is based on the observation that only 22 percent of all alcohol-dependent people seek help within any 1-year period, and fewer than one drug abuser in eight receives formal treatment for alcohol or other drug dependence (Keeffe 1997).
The suitability of ALD patients for OLT also must be considered in the context of the three principles of organ and tissue allocation identified by UNOS (Ethics Committee, UNOS 1992). First, the principle of medical utility requires that organs be allocated to those patients who are likely to experience the maximum medical benefit. This requirement is well satisfied by patients with ALD. Second, the principle of justice requires that equal respect and concern be given to all patients in need of an organ or tissue. This principle generates some ethical questions regarding the potential wastage of organs by transplantation in patients who may "voluntarily" revert to alcoholism. Third, the principle of autonomy requires that the personal choices of the patients be respected. In this regard, the UNOS Ethics Committee holds the view that a person's past behavior (including alcohol consump tion) should not be considered as an exclusion criterion for OLT.
There is no one-to-one correlation between alcoholism and ALD (Benjamin 1997). Only a minority of alcoholics develop ALD and may require OLT; conversely, many patients diagnosed with ALD do not meet the criteria for alcoholism. However, the indiscriminate allocation of a donor liver to an alcoholic who may relapse and thus endanger the function of the transplanted organ is not justifiable to the general public. It is important to remember that the gen eral public makes up the donor pool and may be discouraged from organ donation by a policy of equal trans plantation for alcoholics and nonalco holics. Thus, clinicians must make an effort to identify OLT candidates among the ALD patients who are at low risk for relapse. Moreover, additional educa tion of the public is necessary to dis place the stigma for OLT in alcoholics and to increase organ donation.

Future Directions
Because outcome after liver transplan tation, particularly the risk of relapse, is such an important concern in patients with ALD, identifying the factors that could indicate the most suitable candi dates for OLT is a highly desirable goal of research (Li 1997). The following lines of inquiry show promise in this regard: • Studies have identified genetic char acteristics that influence alcohol intake. Additional in-depth analyses are needed to determine the specific influences of these genes on the development of ALD or on the risk of alcohol relapse after OLT.
• Genetic factors may determine a person's susceptibility to developing liver damage after alcohol consump tion or to becoming alcohol depen dent. Such possible factors should be investigated further, because transplanting a new liver might alter or negate the genetic influence. For example, a patient with a high sus ceptibility to ALD might not be as susceptible to ALD after OLT even if he or she returned to heavy drink ing because the new liver would be governed by its own set of genetic factors. Conversely, if genetic factors determining alcohol metabolism by the liver play a role in maintaining alcohol dependence, then OLT might "cure" the addiction.
• Researchers must develop better means of identifying ALD patients who are at risk of relapse after OLT. With better identification methods, transplant centers could focus their resources on this rather small group of patients before OLT in an effort to prevent subsequent relapses. Furthermore, research assessing vari ous treatment programs may iden tify those approaches that best improve abstinence rates after OLT.
• Currently no definite blood tests (i.e., biochemical markers) can iden tify relapses after OLT. Isolated ele vations in a liver enzyme called gamma-glutamyl transpeptidase without concomitant elevation of another enzyme, called alkaline phosphatase, may serve as a surro gate marker of relapse (Pappo et al. 1995). Further research directed at identifying a marker that can indi cate abstinence over a period of time would be valuable for monitoring the patients' drinking behavior before and after OLT.
• Investigators must further evaluate the outcome of liver transplantation in patients with severe alcoholic hepatitis; currently these patients rarely are considered for an OLT (because they usually do not have enough time to prove sobriety).

Conclusions
OLT currently is the only definitive treatment for liver failure, including ALD. Because of the shortage of donated organs, however, OLT in patients with ALD remains controver sial, mainly out of concerns that the transplanted liver could be "wasted" on a patient who eventually relapses to drinking, thereby damaging the trans planted liver. To address this concern, transplant centers generally perform a multidisciplinary screening procedure before the transplant to identify psy chosocial predictors of relapse and select suitable ALD patients for OLT. Higher survival rates and lower relapse rates than expected in ALD patients after OLT have encouraged many transplant centers to reevaluate their criteria for these patients. As a result, many transplant centers currently do not require that ALD patients com plete a 6-month abstinence period before being placed on a transplant list. Nevertheless, future studies should focus on identifying patients at risk for relapse, so that preventive and thera peutic interventions can be selectively targeted to these patients. The ethical debate regarding the jus tification of OLT in patients with ALD continues, although this subject is less controversial than in the past. Further education of the public regarding the outcomes of liver transplantation in ALD patients should help eliminate the stigma and misapprehensions associated with ALD in the context of OLT and could increase organ donation rates. ■